Oligonucleotide Polymer Conjugates for Targeted Delivery
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Solution Overview
Problem
Current delivery systems for oligonucleotides, such as siRNA and ASOs, face challenges in achieving efficient intracellular delivery and stability, particularly for cancer and infectious disease treatments, with viral carriers posing safety risks and non-viral carriers having low delivery efficiency and stability issues.
Innovation Solution
Development of a therapeutic drug structure comprising biocompatible hydrophilic and hydrophobic polymer compounds bonded to oligonucleotides, including a receptor-specific ligand, to enhance intracellular delivery efficiency and stability, forming nanoparticles that target specific cells via receptor-mediated endocytosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If viral carriers are used for oligonucleotide delivery, then transfection efficacy is improved, but safety risks (immunogenicity and oncogenicity) increase
Solution Approach 1:
The patent replaces permanent, integrated viral vectors with temporary, non-viral nanoparticle carriers that can be easily synthesized and discarded after delivery. These nanoparticle carriers provide the necessary transfection function without the persistent safety risks of viral integration into host genomes.
Solution Approach 2:
The invention creates composite nanoparticle carriers combining multiple materials (e.g., polymers, lipids, or inorganic materials) with oligonucleotides. This composite structure achieves high transfection efficacy through optimized material properties while avoiding the immunogenicity and oncogenicity of viral carriers.
2Object-affected harmful factors
If non-viral carriers are used for oligonucleotide delivery, then safety is improved, but intracellular delivery efficiency decreases
Solution Approach 1:
The patent optimizes multiple parameters of non-viral carriers including particle size (typically 50-200 nm), surface charge (positive or neutral), hydrophilicity/hydrophobicity balance, and chemical composition to enhance cellular uptake. These parameter optimizations enable non-viral carriers to achieve delivery efficiency comparable to or exceeding viral carriers while maintaining safety.
Solution Approach 2:
The invention introduces local functional modifications to non-viral carriers, such as attaching cell-penetrating peptides, ligands for receptor-mediated endocytosis, or charge-modifying groups at specific locations on the carrier surface. These localized enhancements improve intracellular delivery efficiency without compromising the overall safety profile of non-viral carriers.
3Duration of action of stationary object
If hydrophilic materials are coated on nanoparticle surface, then circulation time in blood is improved, but endocytosis efficiency decreases
Solution Approach 1:
The patent implements a heterogeneous surface composition where hydrophilic materials (e.g., PEG) are distributed in a controlled manner to provide blood circulation stability, while localized hydrophobic regions or cell-penetrating motifs are positioned to facilitate endocytosis. This spatial differentiation of surface properties resolves the contradiction between circulation time and endocytosis efficiency.
Solution Approach 2:
The invention designs nanoparticle carriers with dynamic surface properties that can change in response to physiological conditions. For example, the carrier may present a hydrophilic surface in circulation to avoid immune clearance, then undergo conformational changes or surface reorganization at the cellular level to expose hydrophobic or cell-penetrating regions that enhance endocytosis.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The approach significantly improves the intracellular delivery and stability of oligonucleotides, allowing for effective targeting and treatment of diseases at lower concentrations, reducing non-specific distribution and enhancing therapeutic efficacy.
Implementation Method 1
a receptor-specific ligand having the property of enhancing internalization of the target cell by receptor-mediated endocytosis (RME)
Implementation Method 2
comprising a hydrophilic material and a hydrophobic material bonded to both ends of the ASO
Data Source
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AI summary
The present invention provides a double-stranded RNA structure, which comprises a polymer compound covalently bonded to a double-helix oligo RNA useful for the treatment of diseases, particularly cancer, in order to enhance the delivery of the double-helix oligo RNA, and further comprises a target-specific ligand bonded thereto, a preparation method thereof, and a technique of delivering the double-helix oligo RNA in a target-specific manner using the RNA structure. A nanoparticle composed of the ligand-bonded double-helix oligo RNA structures can efficiently deliver the double-helix oligo RNA to a target, and thus can exhibit the activity of the double-helix oligo RNA even when the double-helix oligo RNA is administered at a relatively low concentration. Also, it can prevent the non-specific delivery of the double-helix oligo RNA into other organs and cells. Accordingly, the ligand-bonded double-stranded RNA structure can be used for the treatment for various diseases, particularly cancer, and can also be effectively used as a new type of double-helix oligo RNA delivery system. Particularly, the ligand-bonded double-stranded RNA structure can be effectively used for the treatment of diseases, including cancer and infectious diseases. Moreover, the present invention relates to a hybrid conjugate, which comprises a hydrophilic material and hydrophobic material bonded to both ends of an antisense oligonucleotide (ASO) by a covalent bond in order to enhance the in vivo stability of the ASO, a method for preparing the hybrid conjugate, and a nanoparticle composed of the conjugates. The ASO-polymer conjugate according to the invention can increase the in vivo stability of the ASO, making it possible to efficiently deliver the therapeutic ASO into cells. Also, the ASO-polymer conjugate can exhibit the activity of the ASO even when it is administered at a relatively low concentration.